tbuckley/cabot-search huggingface dataset:
Abstract 3870: TNF-MK2 signaling drives protective autophagy following MAPK pathway inhibition in pancreatic cancer
Authors: Iftikhar Ali Khawar, Qing Wei, Timothy Hung-Po Chen, Lin Lin, Patrick M. Grierson, Kian-Huat Lim
Journal: Cancer Research (2023)

Abstract Targeting the oncogenic KRAS-RAF-MEK-ERK (MAPK) pathway has remain unsuccessful in the clinic for patients with pancreatic ductal adenocarcinoma (PDAC), a highly lethal cancer with few effective treatment options. To identify novel, effective therapeutic strategies, we investigated the impact of MEK and ERK inhibitors on production of inflammatory cytokines in PDAC cells. We found that both MEK and ERK inhibitors dramatically upregulated production of TNF, leading to activation of multiple TNF signaling pathways which include the pro-death and pro-survival NF-kB and p38.MK2 cascades. Silencing of TNF receptor 1 (TNFR1) abrogated the pro-apoptotic effect of MAPK inhibitors, suggesting that pro-death effect driven by TNF signaling is required for the therapeutic effect of MAPK inhibitors. However, targeting the NF-kB and MK2 pathways greatly augment the suppressive effect of MAPK inhibitors. Notably, the mechanisms via which MK2 promotes PDAC cell survival are mediated through phospho-activation of Heat shock protein 27 (Hsp27) and Beclin1, a critical mediator of autophagy. Intriguingly, silencing of TNFR1 abrogated induction of proactive autophagy following MAPK inhibition, strongly suggesting autocrine signaling as the inciting event of autophagy. Mechanistically, we showed that TNF signaling upregulate unfolded protein response (UPR) in PDAC cells, which is required for autophagy induction. Targeting MK2 abrogated transcription of key UPR genes and blocks subsequent autophagy. The combination of MK2 inhibitor ATI-450 and ERK inhibitor ulixertinib was more effective in curbing the growth of PDAC patient-derived xenograft in vivo and prolonged the survival of autochthonous PDAC mice (KPC model). Overall, our study provided novel insights on the mechanisms that drive protective autophagy following MAPK pathway inhibition and a rationale and feasible therapeutic combination that can be tested in clinical trials for PDAC patients. Citation Format: Iftikhar Ali Khawar, Qing Wei, Timothy Hung-Po Chen, Lin Lin, Patrick M. Grierson, Kian-Huat Lim. TNF-MK2 signaling drives protective autophagy following MAPK pathway inhibition in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3870.
Abstract 1451: Cognition-mediated transcriptomic signature associated with androgen deprivation therapy in prostate cancer
Authors: Shiv Shankar Verma, Eswar Shankar, Vaibhav Singh, Vijay Krishna, Sanjay Gupta
Journal: Cancer Research (2023)

Abstract Androgen deprivation therapy (ADT) is the mainstay treatment for non-metastatic and metastatic hormone-sensitive prostate cancer. Long-term ADT treatment results in adverse side-effects in patients including depression, memory loss, cognitive decline, and dementia. We aimed to identify critical molecules that could provide link between brain-related changes and pathological mechanisms responsible for cognitive decline in prostate cancer patients on ADT protocol. For these studies, gene expression data (GSE150807 and GSE151083) of human prostate cancer cells exposed to enzalutamide emulating ADT protocol was used to identify differential expression of genes at the transcript level. RNA sequencing analysis identified 9409 and 7757 differentially expressed genes (DEGs) in LNCaP and C4-2B enzalutamide exposed cells at p-value &amp;lt; 0.0005 and FDR&amp;lt; 0.05. In both cell lines, neuronal receptor signaling pathway was significantly overrepresented at 0.05 FDR-adjusted p-value (q-value). The genes associated with neuronal receptor signaling pathway belong to the ligand-gated ion channel and G-protein coupled receptors. Validation studies using brain glial cells treated with enzalutamide showed significant upregulation (p-value 0.001) of GABRB1, GABRA3, GABBR2 (GABA receptors/ligand-gated ion channel), BDNF (brain-derived neurotrophic factor), IFNB1 (interferon beta 1), NR3C1 (nuclear receptor subfamily 3 group c member/glucocorticoid receptor), ATGR1 (type-1 angiotensin II receptor), GRIN1 (glutamate ionotropic receptor NMDA type submit 1/ligated-gated ion channel), GRIN2D (glutamate ionotropic receptor NMDA type submit 2D/ligated-gated ion channel). In brain neuronal cells, enzalutamide exposure resulted in increased expression of NR3C1 whereas GABA/ligand-gated ion channel and others were downregulated and/or statistically non-significant. Further analysis using DisGenET (cytoscape) highlighted ATGR1, GABRB1, GRIN1, GRIN2D, and NR3C1 association with neuronal diseases including cognition disorder, forgetfulness, depressive mood, and others. The results of our study provide the first proof of evidence linking cognitive decline, depression, memory loss, and other neurological disorder more likely to develop in prostate cancer patients undergoing long-term androgen deprivation therapy. Citation Format: Shiv Shankar Verma, Eswar Shankar, Vaibhav Singh, Vijay Krishna, Sanjay Gupta. Cognition-mediated transcriptomic signature associated with androgen deprivation therapy in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1451.
Abstract 2449: p38β promotes cancer stemness and chemoresistance in hepatocellular carcinoma
Authors: Ianto Bosheng Huang, Yunong Xie, Tin Lok Wong, Terence Kin Wah Lee, Jing-Ping Yun, Stephanie Kwai Yee Ma, Man Tong
Journal: Cancer Research (2023)

Abstract Protein kinases control a variety of oncogenic functions through a phosphotransfer dependent signal transduction cascade in cancers where potent and selective inhibitors could be developed with favorable pharmaceutical properties. In hepatocellular carcinoma (HCC), increasing evidence suggested that cancer stemness is a driving force of therapy resistance which is tightly controlled by kinase-dependent signaling cascades. However, there are still limited druggable kinase targets that are developed to combat cancer stemness and therapy resistance for HCC treatment. To identify potential kinase targets which promote stemness, survival and therapy resistance in HCC, two datasets profiling kinase genes which are important for HCC survival and chemoresistance in HCC spheres were compared. p38 MAPK beta (p38β) was found to be a common top-ranked kinase important for these functions. Clinically, biopsies of human HCC showed high expression of total and activated forms of p38β, suggesting that p38β could be a potential therapeutic target in HCC. Functionally, we demonstrated that p38β promoted HCC tumor initiation, self-renewal and resistance towards chemotherapy by cisplatin. Using tandem affinity purification coupled with mass spectrometry, we identified BiP, which is a chaperone protein, as a novel binding partner of p38β. Subsequent mechanistic validation and mass spectrometry analysis showed that p38β directly phosphorylates BiP at a previously unrecognized phosphorylation site. Rescue experiments with BiP mutation and inhibition abrogated the stemness and chemoresistant properties observed in p38β overexpressing HCC cells. Taken together, we identified and characterized p38β and its direct phosphorylation target BiP as critical regulators for promoting cancer stemness and chemoresistance in HCC. Citation Format: Ianto Bosheng Huang, Yunong Xie, Tin Lok Wong, Terence Kin Wah Lee, Jing-Ping Yun, Stephanie Kwai Yee Ma, Man Tong. p38β promotes cancer stemness and chemoresistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2449.
Abstract 2469: Investigating the effects of <i>in vivo</i> silencing of RBBP6 gene on tumor growth in the FVBN-Tg(MMTV PyVT)634MulJ breast cancer mouse model
Authors: Pontsho Moela, Mayur Govender, Melvin Ambele
Journal: Cancer Research (2023)

Abstract Breast cancer is one of the most common causes of cancer mortality, with close to two million new cases and just over 600 000 cancer deaths projected in 2022 in the United States of America alone. Identifying prognostic markers for breast cancer is critical to reducing these numbers. Retinoblastoma binding protein 6 (RBBP6) is considered a potential cancer biomarker due to its association with cell proliferation and the fact that it is overexpressed at breast cancer sites where there is marked apoptosis and elevated p53. More information is emerging regarding the role of RBBP6 in cancer treatment, specifically its potential to sensitize cancer cells to radiation and certain chemotherapeutic agents. In vivo studies on RBBP6 in breast cancer mouse models are limited. Our study aims to investigate the molecular function and the prognostic potential of RBBP6 in breast cancer using MCF-7 cell line and the FVB/N-Tg(MMTV PyVT)634Mul/J breast cancer mouse model. The expressional effects of RBBP6 on cancer cell proliferation and metastatic tumour growth in cancer mice were examined in vitro and in vivo using RT-PCR, western blotting, and tumour size monitoring. The results demonstrate that RBBP6 mRNA expression was significantly higher in both local and distal tumours with a corresponding overexpression of angiogenic and metastatic key markers, VEGF164 and CD31, respectively. In addition, tumour growth reduced gradually over a period of two weeks in response to RBB6 gene knockdown. Our study indicated that RBBP6 may be a potential metastatic marker in breast tumours. Citation Format: Pontsho Moela, Mayur Govender, Melvin Ambele. Investigating the effects of in vivo silencing of RBBP6 gene on tumor growth in the FVBN-Tg(MMTV PyVT)634MulJ breast cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2469.
Abstract 2462: AXL-WRNIP1 mediated replication stress response aids metastatic latency and relapse
Authors: Mauricio Marquez-Palencia, Srinivas Malladi
Journal: Cancer Research (2023)

Abstract Metachronous brain metastases, the primary cause of morbidity and mortality in HER2+ breast cancer patients arise from latent residual cells that resist systemic therapies. AXL, a receptor tyrosine kinase, is enriched in metachronous brain metastatic lesions from HER2+ breast cancer patients and in latent metastatic models. In contrast to its known function at the cell surface, AXL is localized to the nucleus and interacts with WRNIP1. Moreover, we show AXL depletion results in an increased replication stress and reduced survival of brain-tropic latent residual and metastatic cells. Furthermore, administration of BGB324 as a neoadjuvant sensitives brain metastatic lesions to targeted therapy. Our findings suggest targeting AXL is a viable option to eradicate residual brain metastatic cells and limit relapses in HER2+ breast cancer patients. Citation Format: Mauricio Marquez-Palencia, Srinivas Malladi. AXL-WRNIP1 mediated replication stress response aids metastatic latency and relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2462.
Abstract 3153: Prediction of metabolites from cancer-associated fibroblasts that can have profound effects on cancer cells
Authors: Hae Deok Jung, Yoo Jin Sung, Jae Yong Ryu, Hyun Uk Kim
Journal: Cancer Research (2023)

Abstract Cancer-associated fibroblasts (CAFs) are the most abundant component of tumor microenvironment (TME) that is an ensemble of non-cancerous cells surrounding cancer cells. In particular, CAFs are known to have tumor-assisting functions, which may promote active growth and survival of the interacting cancer cells through their metabolic reprogramming despite being in a harsh environment (e.g., hypoxia or low pH). In this regard, CAF-derived metabolites are expect to have profound effects on metabolism of the cancer cells. To identify novel CAF-derived metabolites that may heavily influence the cancer cells, CAF-specific genome-scale metabolic models (GEMs) were reconstructed and simulated. GEM is a computational model that can predict a metabolic state in a cell-specific manner by integrating omics data (e.g., RNA-seq data). In this study, a total of six GEMs were reconstructed by integrating RNA-seq data from one normal fibroblast, originating from pancreas, and five CAFs associated with breast, colon, skin, lung, and pancreatic tumors. Simulation of the GEMs predicted 20 metabolites that appeared to be heavily used by all the five CAF GEMs in comparison with the one normal fibroblast GEM. Such metabolites were expected to be significantly associated with establishment of TME that is favorable for the cancer cells’ growth. Some of these metabolites are associated with pyrimidine metabolism, fatty acid metabolism, and primary bile acid biosynthesis. Upon experimental validation, the predicted metabolites are expected to help better understand CAFs and TME in terms of metabolites, and also provide clues for identifying effective drug targets for cancer treatment. Citation Format: Hae Deok Jung, Yoo Jin Sung, Jae Yong Ryu, Hyun Uk Kim. Prediction of metabolites from cancer-associated fibroblasts that can have profound effects on cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3153.
Abstract 4067: RNA primed SMAR-TTMcells against multiple driver mutations, all HLA's, designed for first line therapy
Authors: Farzonai Muzaffar, David Ryan, Walter Barry, Abenezer Abera, Alfred E. Slanetz
Journal: Cancer Research (2023)

Abstract Immune checkpoint inhibitors, such as anti-PD1 antibodies, have revolutionized cancer immunotherapy. Their success demonstrates that a patient’s own T cells recognize and treat cancer. However, anti-PD1 therapy is most effective in the treatment of cancers with high mutational burden, ~5% of all malignancies. Therefore, an alternative strategy is necessary to target cancer with lower mutational burden (the other ~95%). Importantly, the efficacy of PD-1 blockade is associated with the recruitment of new T cells from the blood rather than the activation of pre-existing tumor infiltrating lymphocytes (Yost K.E., et al. Nat. Med. 2019). Our approach is to use RNA to prime and expand T cells from the blood to cancer-specific mutations ex vivo. We can generate T cell populations reactive to as few as 8 and as many as 40 cancer-specific mutant proteins in a single production run. In vitro, these T cells have mutation-specific cytotoxicity and do not kill the normal cells. These T cells express homing receptors that allow them to infiltrate the tumor and express high levels of TNFα and IFNγ, both of which are associated with effective tumor cytotoxicity and pro-inflammatory modification of the tumor microenvironment (TME). The predominant immunophenotype of these cells is consistent with central and effector memory, CD4+ and CD8+ T cells, with almost no regulatory or exhausted T cells. We believe these T cells can be used as a cellular therapy in conjunction with, or as an alternative to, immune checkpoint inhibitors to treat lower mutational burden cancers that comprise most patients’ tumors. Citation Format: Farzonai Muzaffar, David Ryan, Walter Barry, Abenezer Abera, Alfred E. Slanetz. RNA primed SMAR-TTMcells against multiple driver mutations, all HLA's, designed for first line therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4067.
Abstract 424: RTK inhibitor resistance in NSCLC harboring MED12 mutation is overcome by only blocking MEK signaling, not AKT due to mutated MED12-induced YAP-PTEN dysregulation
Authors: Hyun-Min Ryu, Deokhoon Kim, Shinkyo Yoon, Ho-Su Lee, Eunjin Lee, Chang Hoon Lee, Wanlim Kim, Seyoung Seo, Kyung Hae Jung, Sook Ryun Park, Sang-We Kim, Kang-Seo Park, Dae Ho Lee
Journal: Cancer Research (2023)

Abstract The advent of receptor tyrosine kinase inhibitors (RTKi) are important contributions to treat NSCLC patients harboring genetic aberration effectively. Nevertheless, the emergence of acquired or intrinsic RTKi resistance by other RTK activation bypass finally limits their efficacy. First of all, in this study, we identified MED12 mutation in TKI-resistant NSCLC cells based-on NGS analysis. Although MED12 was known to controls the response to multiple cancer drugs through regulation of TGF-beta receptor signaling reportedly, we additionally found that MED12 mutation activates not only TGF-beta receptor not also other ones, such as EGFR, meaning that blocking TGF-beta receptor or EGFR alone may not effective to overcome MED12 mutation-induced RTKi resistance. To overcome the RTKi resistance in NSCLC harboring MED12 mutation, we elaborated the two downstream signaling of RTK in MED12 knock-out NSCLC cells and observed that PI3K/AKT signaling is downregulated but MEK/ERK signaling is upregulated. We observed that only MEK inhibitor (MEKi), not PI3K/mTOR inhibitor, shows effective anti-cancer effect. Therefore, we explored why MEKi alone is effective in RTKi resistant NSCLC cells harboring MED12 mutation and presented that MED12 mutation directly suppressed activation of YAP via blocking a large mediator complex of MED12, MED13, CDK8 and CCNC, thereby increasing PTEN expression by inhibition of miR-29 expression. Increased PTEN inhibits reactivation of PI3K/AKT pathway. In conclusion, we first identified that MED12 mutation induces RTKi resistance though activating other RTKs, such as TGF-beta receptor or EGFR, and blocks PI3K/AKT pathway via dysregulation of YAP/PTEN/AKT interaction. Therefore, among two downstream signaling of RTK, activated MEK/ERK pathway can be a definitive target enough to overcome RTKi resistant NSCLC patients harboring MED12 mutation and MEKi could be a primary treatment option for resistant patients harboring MED12 mutation among NSCLC patients with repetitive recurrence of RTKi resistance by another RTK activation bypass. Citation Format: Hyun-Min Ryu, Deokhoon Kim, Shinkyo Yoon, Ho-Su Lee, Eunjin Lee, Chang Hoon Lee, Wanlim Kim, Seyoung Seo, Kyung Hae Jung, Sook Ryun Park, Sang-We Kim, Kang-Seo Park, Dae Ho Lee. RTK inhibitor resistance in NSCLC harboring MED12 mutation is overcome by only blocking MEK signaling, not AKT due to mutated MED12-induced YAP-PTEN dysregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 424.
Abstract 4566: 3D cancer cell-fibroblast heterospheroids forming tumor-like microenvironments are valuable tools to study immune cell infiltration and as pre-clinical drug testing models
Authors: Boye Schnack Nielsen, Natasha H. Madsen, Jesper Larsen, Hjalte M. Larsen, Monika Gad, Kim Holmstrom
Journal: Cancer Research (2023)

Abstract 3D cancer cell cultures have enabled new opportunities for replacing compound testing in experimental animals and provide a basis for high content work-flows for drug testing. Here we present data obtained from 3D multicellular tumor spheroids (MCTS) composed of cancer cell lines, fibroblasts and macrophages. We cultured HT29 and SW480 CRC cell lines (as well as others) with fibroblasts and obtained heterospheroids that could be evaluated in cell viability and apoptosis assays, by flow cytometry and high content imaging (HCI). In addition, mature MCTS were embedded in paraffin and used for traditional biomarker characterization using immunohistochemistry and in situ hybridization. The cancer cell x fibroblast interactions promoted a tumor-like microenvironment that recruited monocytes isolated from primary donors. FACS analysis indicated that the infiltrating monocytes polarized into CD163-positive M2 macrophages in HT29 MCTS, and in pancreatic MIA PaCa-2 MCTS, using Pexidartinib and anti-CSF1R mAb, we found that monocyte infiltration was strongly CSF1R dependent. Preliminary data suggest that also infiltration of T cells into the heterospheroids is possible, thus making the models useful for the study of immune cell infiltration. Whole transcriptomic analysis of mono-cultures of SW480 cancer cells and fibroblast spheroids and co-cultures (MCTS) identified traditional cell-type-related transcripts as well as a group of de novo expressed genes induced by co-culturing, such as serpin peptidase inhibitor clade A1 (serpinA1) and inhibin-β A (INHBA). The NGS analysis as well as immunohistochemical staining also showed that SW480 expressed high levels of P-glycoprotein (P-Gp, MDR1) in contrast to the fibroblasts. On the other hand, the HT29 MCTS were negative for P-Gp. Histological analysis and the apoptosis assay showed that the fibroblasts were more sensitive to 5FU and cisplatin treatment than the cancer cells. We are currently testing if the P-Gp inhibitor, PSC-833, can re-sensitize the cancer cells to 5FU and cisplatin. In conclusion, we have developed 3D multicellular heterospheroids mimicking tumor-like microspheres that can be used for drug testing of traditional drug compounds, biologics and even immunotherapeutic agents. Citation Format: Boye Schnack Nielsen, Natasha H. Madsen, Jesper Larsen, Hjalte M. Larsen, Monika Gad, Kim Holmstrom. 3D cancer cell-fibroblast heterospheroids forming tumor-like microenvironments are valuable tools to study immune cell infiltration and as pre-clinical drug testing models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4566.